Summary: Otitis media (OM) is the most common childhood bacterial infection and the leading cause of conductive hearing loss. It remains a major health problem and a substantial socioeconomic burden. Nontypeable Haemophilus influenzae (NTHi) is a major bacterium causing OM. Currently there is no effective vaccine available for NTHi and inappropriate systemic use of antibiotics increased antibiotic resistance. There have been no available non-antibiotic agents effectively permeating across intact tympanic membrane (TM). The major hallmarks of OM are overactive inflammation and mucus overproduction, which play a critical role in conductive hearing loss in children with delayed speech and language development. Thus there is currently an urgent need for developing innovative therapeutic agents to suppress inflammation and mucus overproduction and improve hearing. Moreover, non-invasive ototopical administration of therapeutic agents is highly desirable as it allows achieving much higher local concentration in middle ear and has much less adverse effects compared with systemic administration. Recently, taking advantage of drug repositioning strategy (Innovation), we identified the novel therapeutic effects of two existing drugs Vinpocetine (anti-stroke drug) and Roflumilast (anti-COPD drug) in mouse models of OM. Interestingly, our exciting preliminary studies demonstrate that non-invasive post-infection ototopical administration of Vinpocetine and Roflumilast formulated in hydrogel containing chemical permeation enhancers (CPEs) inhibited NTHi-induced middle ear inflammation, suppressed mucus overproduction, enhanced NTHi-induced up-regulation of bactericidal ?-defensin and improved bacterial clearance, and also improved hearing in well-established mouse OM models (both acute and chronic OM) with intact tympanic membrane which represents most common clinical situations of OM children (Innovation & Significance). Encouragingly, no detectable ototoxicity was observed with any of these treatments. These encouraging preliminary data have demonstrated the significant therapeutic potential of these two highly promising repurposed drugs, and thus laid a solid foundation for us to fully test their efficacy and toxicity in OM. Two Specific Aims will be pursued to determine the therapeutic efficacy of CPE-mediated non-invasive ototopical administration of Vinpocetine (Aim 1) or Roflumilast (Aim 2) in suppressing inflammation and mucus overproduction, improving bacterial clearance and also hearing in acute and chronic mouse models of otitis media. These studies may lead to the development of novel and non-invasive ototopical therapeutic agents for OM (Translational and Therapeutic Significance).